Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy

• DOI: 10.1038/ncomms7220
• Publication Date: 2015-02-05T12:18:42Z
• Authors: Hilary A. Kenny; Madhu Lal-Nag; Erin A. White; Min Shen; Chun-Yi Chiang; Anirban K. Mitra; Yilin Zhang; Marion Curtis; Elizabeth M. Schr...; Sam Bettis; Ajit Jadhav; Matthew B. Boxer; Zhuyin Li; Marc Ferrer; Ernst Lengyel
• Keywords: Benzophenanthridines; Escin; 0303 health sciences; Biguanides; Mice, Nude; Antineoplastic Agents; Epithelial Cells; Fibroblasts; Isoquinolines; Coculture Techniques; Extracellular Matrix; High-Throughput Screening Assays; 3. Good health; Inhibitory Concentration 50; Mice; 03 medical and health sciences; Cell Movement; Cantharidin; Cell Adhesion; Animals; Humans; Female; Cell Proliferation

The tumour microenvironment contributes to cancer metastasis and drug resistance. However, most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers. Here we show that a multilayered culture containing primary human fibroblasts, mesothelial cells and extracellular matrix can be adapted into a reliable 384- and 1,536-multi-well HTS assay that reproduces the human ovarian cancer (OvCa) metastatic microenvironment. We validate the identified inhibitors in secondary in vitro and in vivo biological assays using three OvCa cell lines: HeyA8, SKOV3ip1 and Tyk-nu. The active compounds directly inhibit at least two of the three OvCa functions: adhesion, invasion and growth. In vivo, these compounds prevent OvCa adhesion, invasion and metastasis, and improve survival in mouse models. Collectively, these data indicate that a complex three-dimensional culture of the tumour microenvironment can be adapted for quantitative HTS and may improve the disease relevance of assays used for drug screening.